Voriconazole is a commercially marketed pharmaceutically active substance known to be useful for the treatment of some fungal infections. Voriconazole has an empirical formula of C16H14F3N5O and a molecular weight of 349.3. Voriconazole is the international common accepted name for (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, which is represented in formula (I).

Voriconazole is a triazole antifungal agent. Voriconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Compared to fluconazole, voriconazole inhibits P45014DM to a greater extent. This inhibition is dose-dependent. Voriconazole is active following both oral and intravenous administrations. Oral (200 mg twice daily) and intravenous (3 to 6 mg/kg every 12 h) doses of Voriconazole have produced favorable response. Voriconazole is marketed under the name VFEND®. The VFEND® products are available as an I.V. solution, a powder for oral suspension (and hence an oral suspension), and film coated tablets for oral administration. VFEND® is for the treatment of some fungal infections. VFEND® is said to help fight life-threatening fungal infections, such as fungal infections in people who have a weak immune system, e.g., patients with cancer or patients who have received an organ or bone marrow transplant. VFEND® is said to have been proven effective against a type of fungus called Aspergillus. The following U.S. patents are listed in the U.S. FDA's Orange Book as to VFEND®: U.S. Pat. No. 5,116,844; U.S. Pat. No. 5,134,127; U.S. Pat. No. 5,364,938; U.S. Pat. No. 5,376,645; U.S. Pat. No. 5,567,817; U.S. Pat. No. 5,773,443; and U.S. Pat. No. 6,632,803. Formulations, doses and uses of Voriconazole as available commercially in the VFEND® product, and as in these herein cited US patents may be employed in the practice of the herein invention.
The '817 patent refers to different routes of synthesis for the preparation of Voriconazole and other triazole derivatives. One of these synthetic processes, as shown in schemes 1 and 2, comprises reacting 4-chloro-6-ethyl-5-fluoropyrimidine (compound II), which is deprotonated using a suitable base, such as LDA, with 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (compound III) in tetrahydrofuran. The product obtained in the above reaction is the following chloroderivative 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (compound IV) as a mixture of 4 stereoisomers, that is, 2 enantiomeric pairs, enantiomeric pair A (2R,3R/2S,3S) and enantiomeric pair B (2R,3S/2S,3R).

The chromatographic treatment of the two pairs of enantiomers, A and B, allows the separation of enantiomeric pair B from enantiomeric pair A. Enantiomeric pair B of chloroderivative of formula (IV) is used then for obtaining Voriconazole (compound I).
Preparation of Racemic Voriconazole (Compound V) from Enantiomeric Pair B of chloroderivative of formula (IV) by classical hydrogenation conditions using Pd/C and sodium acetate in ethanol is shown in scheme 2. Resolution of the obtained racemic Voriconazole (compound V) is performed with (1R)-(−)-10-camphorsulfonic acid (CSA) in 38 volumes of methanol to give (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol (1R)-(−)-10-camphorsulfonate (compound VI), that is, Voriconazole (1R)-(−)-10-camphorsulfonate, as hemimethanolate having a melting point of 176° C. Voriconazole (compound I) is isolated from Voriconazole (1R)-(−)-10-camphorsulfonate (compound VI) using dichloromethane and saturated aqueous sodium bicarbonate and final evaporation of the organic extract. The obtained Voriconazole shows a melting point of 127° C.

Another process for the preparation of Voriconazole (compound I) is shown in scheme 3 in U.S. Pat. No. 6,586,594 (the '594 patent). The starting materials for the preparation of chloroderivative of formula (IV) are the same as in the '817 patent, but the pyrimidine derivative (compound II) is brominated at the methylene position of the ethyl group and the resulting bromopyrimidine derivative (compound VII) is used for the preparation of chloroderivative of formula (IV) by reaction with 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (compound III), as shown in scheme 3. In this case, the reaction is performed in the presence of zinc, iodine and/or a Lewis acid and an aprotic organic solvent, optionally also in the presence of lead. Using this process chloroderivative of formula (IV) as enantiomeric pair B is obtained with high stereoselectivity. Then, Voriconazole (compound I) is prepared from chloroderivative of formula (IV). The chloroderivative of formula (IV) can be used for the next step as free base or as acid addition salt, in particular, hydrochloride salt. In the '594 patent classical hydrogenation conditions using Pd/C and sodium acetate in ethanol is described. In '594 patent, catalytic transfer hydrogenation with HCOONH4 is also described and exemplified starting from chloroderivative of formula (IV) as hydrochloride salt. In this case, two options are possible: direct dechlorination by using 4 equivalents of HCOONH4 or previous alkaline treatment of the hydrochloride with NaOH in dichloromethane as extraction solvent and exchange of solvent with methanol. Resolution of racemic Voriconazole (compound V) is carried out with (1R)-(−)-10-camphorsulfonic acid ((−)-CSA) in a mixture (30 volumes) of acetone (22.5 volumes)/methanol (7.5 volumes) or in acetone (aprox. 10 volumes) followed by a treatment in a mixture of methanol and acetone. Voriconazole (compound I) is isolated from Voriconazole (1R)-(−)-10-camphorsulfonate (compound VI) using dichloromethane and 40% aqueous sodium hydroxide solution, evaporation of the organic extract and crystallization with isopropanol. The obtained Voriconazole has a melting point of 133° C.

Polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have different arrangement and/or conformation of the molecules in the crystal lattice. Different polymorphs differ in their physical properties such as melting point, solubility, chemical reactivity, etc. These can appreciably influence pharmaceutical properties such as dissolution rate and bioavailability.
According to example 4ii of the '594 patent Voriconazole (compound I) is obtained with a melting point of 133° C. after a treatment with isopropanol followed by vacuum drying at 50° C. No polymorphic data are described in the '594 patent. However, this example has been reproduced by the herein inventors and the obtained product shows a X-ray powder diffractogram substantially identical to that of FIG. 1, an Infrared (IR) spectrum substantially identical to that of FIG. 2 and a Differential Scanning Calorimetry (open pan) substantially identical to that of FIG. 9. The obtained polymorphic form is designated herein as polymorphic Form I. FIG. 1 illustrates the X-ray powder diffractogram pattern (2θ) (±0.2°) of Voriconazole Form I comprising peaks at about 6.9°, 13.8°, 14.8°, 18.2°, 19.7°, 24.5°, 27.8° and 35.0°. X-ray powder diffractogram pattern of Voriconazole form I further comprises peaks at about 12.6°, 15.9°, 16.5°, 17.4°, 21.2°, 22.5°, 26.1°, 28.2° and 29.8°. FIG. 9 illustrates the differential scanning calorimetry (open pan) of Voriconazole form I which exhibits an endothermic peak at approximately 130° C.
The European Public Assessment Report for Vfend® of the European Medicine Agency (EMEA) mentions that “investigations into Voriconazole solid-state properties revealed no evidence of either polymorphism or solvates”.
Crystalline polymorphic forms of Voriconazole (1R)-(−)-10-camphorsulfonate (compound VI) have not been reported in the literature. However, Voriconazole (1R)-(−)-10-camphorsulfonate crystal structure is described in the publication Bioorganic & Medicinal Chemistry Letters, 1996, 6, 2031. The corresponding crystal data and atomic positions can be retrieved from the Crystallographic Cambridge Data Base (refcode TUPFOZ). From these data a powder X-ray Diffraction pattern can be simulated, as shown in FIG. 7, assuming CuKα radiation (for instance, using LAZY PULVERIX). This polymorphic form is designated herein as Form A. Voriconazole (1R)-(−)-10-camphorsulfonate Form A obtained by treating racemic Voriconazole (compound V) with (1R)-(−)-10-camphorsulfonic acid ((−)-CSA) in methanol shows a X-ray powder diffractogram substantially identical to that of FIG. 3 and an Infrared (IR) spectrum substantially identical to that of FIG. 4. FIG. 3 illustrates the X-ray powder diffractogram pattern (2θ) (0.2°) of Voriconazole (1R)-(−)-10-camphorsulfonate Form A comprising peaks at about 6.4°, 9.7°, 12.8°, 15.4°, 17.4°, 20.0°, 27.4° and 27.9°. X-ray powder diffractogram pattern of Voriconazole (1R)-(−)-10-camphorsulfonate Form A further comprises peaks at about 7.1°, 12.6°, 13.7°, 14.3°, 16.0°, 18.2°, 19.2°, 21.2°, 21.5°, 23.0°, 23.3°, 23.7°, 25.5° and 29.0°.
Some examples regarding particle size distribution of Voriconazole are found in the literature. U.S. Pat. No. 6,558,435 B2 describes a method of obtaining Voriconazole with an improved particle size from Voriconazole (1R)-(−)-10-camphorsulfonate by a technique consisting in mixing a solution of Voriconazole (1R)-(−)-10-camphorsulfonate in a mixture 50:50 volume ratio of ethanol/water with another solution of a base in such a way that both solutions are conducted separately through individual jets and contacted as jet streams in a vessel. The flow of the two solutions create an impingement zone between the two jets and crystalline material is formed and flowed down to another vessel. The particle size distribution achieved according to this methodology is 90% less than 41 μm and 50% less than 18 μm. It is also mentioned that the specification of product conventionally obtained by jet milling is 90% less than 130 μm and 50% less than 50 μm.
IP.com Journal, 2005, 5(6A), 38 (No. IPCOM000125373D) describes a method of preparing Voriconazole in a crystal habit which is particularly useful for making micronized Voriconazole by an air-jet mill or a pin-mill. Thus, Voriconazole is micronized to a particle size of about 40 μm, preferably about 20 μm.
In Powder Technology, 2004, 143-144, 179-185 nanoindentation of single particles is used as a technique to measure the mechanical properties of powders. Voriconazole with a particle size distribution of 90% less than 250 μm is analyzed. It is also mentioned that Voriconazole is very plastic and elastic.
In Organic Process Research and Development, 2004, 8, 674-679 nanoindentation of single crystals is used to predict milling of pharmaceutical materials including Voriconazole. It is mentioned that Voriconazole is very plastic and difficult to mill and that no size reduction below 250 μm could be obtained under standard mill types so a more energetic milling process is required.